SPINAL NITRIC-OXIDE SYNTHESIS INHIBITION BLOCKS NMDA-INDUCED THERMAL HYPERALGESIA AND PRODUCES ANTINOCICEPTION IN THE FORMALIN TEST IN RATS

To assess the possible role of spinal nitric oxide (NO) synthesis in n ociceptive processing, we examined the effect of intrathecal (i.t.) in jection of arginine analogs that act as alternate substrates for NO sy nthase and thus inhibit NO production. NG-nitro-L-arginine methyl este r (L-NAME) and NG-monomethyl-L-arginine (L-NMMA) produced a dose-depen dent, stereospecific inhibition of the second phase (10-60 min; ED50, 135 and 246 nmol) of the formalin test with minimal effect on the firs t phase (0-9 min; ED50 > 1.1 mumol). The inhibitory action Of L-NAME w as dose-dependently reversed by i.t. L-arginine (ID50, 4.9 mumol) but not by D-arginine (ID50 > 14 mumol). The suppression of the second-pha se formalin response by L-NAME was similar whether administered before or after formalin injection into the rat paw. Spinal administration O f L-NAME (370 nmol), but not D-NAME (3.7 mumol), also blocked thermal hyperalgesia induced by i.t. injection of N-methyl-D-aspartate (NMDA; 6.8 nmol). The effect Of L-NAME was reversed by L-arginine (4.7 mumol) but not with D-arginine (14 mumol). None of the compounds, L-NAME, D- NAME or L-arginine, when injected alone, had any effect on normal ther mal response latencies or on the 52.5-degrees-C hot plate. These studi es indicate that modulation of spinal NO synthesis can diminish the fa cilitated processing of afferent activity which is induced by a contin ued afferent barrage (second phase of the formalin test). This hyperal gesic component appears initiated by the activation of a spinal NMDA r eceptor that, through the generation of NO, leads to the observed augm ented processing of afferent input and the associated hyperalgesic com ponent of the subsequent pain behavior.